The instant invention is directed to a process for the preparation of cell proliferation inhibitors and to intermediates useful in the process.
Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The microtubule system of eucaryotic cells comprises a dynamic assembly and disassembly matrix in which heterodimers of tubulin polymerize to form microtubules in both normal and neoplastic cells. Within neoplastic cells, tubulin is polymerized into microtubules which form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle""s use has been fulfilled. Agents which disrupt the polymerization or depolymerization of microtubules in neoplastic cells, thereby inhibiting the proliferation of these cells, comprise some of the most effective cancer chemotherapeutic agents in use.
While commonly owned U.S. Patent Provisional Application Ser. No. 60/136,542 teaches the preparation of substituted indole cell proliferation inhibitors, the synthesis is not amenable to large-scale preparation. For example, the sulfonylation of N-formylindoline is accomplished using five equivalents of chlorosulfonic acid. Upon workup, the excess chlorosulfonic acid is quenched, causing a vigorous reaction. When conducted on large amounts of material, this procedure becomes hazardous, rendering these conditions impractical for large-scale synthesis. In addition, the oxidation of the indolinesulfonamide to the corresponding indolesulfonamide is accomplished with salcomine in the presence of oxygen. The yield on this reaction is extremely low and the results are often not reproducable, making the procedure inefficient and thus impractical for large-scale synthesis.
As shown by the above examples, there is still a need in the pharmaceutical manufacturing industry for the efficient preparation of substituted indole cell proliferation inhibitors. The instant invention discloses a synthesis of cell proliferation inhibitors which offers higher overall yields and less hazardous conditions, making it amenable to large-scale preparation.
In one embodiment of the instant invention, therefore, is disclosed a process for preparing a compound of formula (5) 
or a therapeutically acceptable salt thereof, wherein
R1 and R5 are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; and
R2, R3, and R4 are independently selected from the group consisting of alkyl and alkoxy;
the process comprising:
(a) reacting N-formylindoline with chlorosulfonic acid and thionyl chloride; and
(b) reacting the product from step (a) with a base and a compound of formula (4) (4). 
In a preferred embodiment of the instant invention is disclosed a process for preparing a compound of formula (5), or a therapeutically acceptable salt thereof, the process comprising:
(a) reacting N-formylindoline with chlorosulfonic acid and thionyl chloride at about 65xc2x0 C. to about 85xc2x0 C. for about 1 to about 5 hours; and
(b) reacting the product from step (a) with a carbonate salt and a compound of formula (4).
In a more preferred embodiment the compound of formula (5) is 1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide.
In another embodiment of the instant invention is disclosed a process for reacting indoline with an N-formylating reagent to provide the N-formylindoline.
In another embodiment of the instant invention is disclosed a process for preparing a compound of formula (7) 
the process comprising:
(a) reacting the compound of formula (5) with a reducing agent; and
(b) reacting the product of step (a) with an oxidizing agent.
In a preferred embodiment of the instant invention is disclosed a process for preparing a compound of formula (7),
the process comprising:
(a) reacting a compound of formula (5) with a reducing agent at about xe2x88x925xc2x0 C. to about 30xc2x0 C. for about 1 to about 5 hours; and
(b) reacting the product of step (a) with an oxidizing agent at about xe2x88x925xc2x0 C. to about 35xc2x0 C. for about 2 to about 14 hours.
In a more preferred embodiment the compound of formula (7) is 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.
In yet a further embodiment of the instant invention is disclosed a process for preparing a compound of formula (7), the process comprising:
(a) reacting the compound of formula (5) with a deformylating agent;
(b) reacting the product from step (a) with an oxidizing agent; and
(c) reacting the product from step (b) with a base and a methylating agent.
In yet an additional embodiment of the instant invention is disclosed a process for preparing a compound of formula (7a) 
the process comprising:
(a) reacting indoline with a formylating agent;
(b) reacting the product of step (a) with chlorosulfonic acid and thionyl chloride;
(c) reacting the product of step (b) with a base and a compound of formula (4);
(d) reacting the product of step (c) with a reducing agent; and
(e) reacting the product of step (d) with an oxidizing agent.
In another embodiment of this aspect of the instant invention disclosed is a process for preparing a compound of formula (7a),
the process comprising:
(a) reacting indoline with a formylating agent;
(b) reacting the product of step (a) with chlorosulfonic acid and thionyl chloride;
(c) reacting the product of step (b) with a base and a compound of formula (4);
(d) reacting the product of step (c) with a deformylating agent;
(e) reacting the product of step (d) with an oxidizing agent; and
(f) reacting the product of step (e) with a base and a methylating agent.
In a further embodiment of the instant invention is disclosed a process for preparing a compound of formula (10a) 
the process comprising:
reacting a compound of formula (7a) with N,N-dimethylaminoacetyl chloride hydrochloride in the presence of N,N-dimethylaminopyridine and diisopropylethylamine.
In another embodiment of the instant is disclosed a compound of formula (I) 
or a therapeutically acceptable salt thereof, wherein
R1, R2, R3, R4, and R5 are previously defined; and
RA is selected from the group consisting of hydrogen, formyl, and methyl.
The instant invention is directed to processes for the preparation of cell proliferation inhibitors and to intermediates which are useful in these processes of preparation. As used in the instant specification the following terms have the meanings specified.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9calkyl,xe2x80x9d as used herein, represents a monovalent group of one to six carbon atoms derived from a straight or branched chain saturated hydrocarbon.
The term xe2x80x9cbase,xe2x80x9d as used herein, represents a reagent capable of accepting protons during the course of a reaction. Examples of bases include carbonate salts such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; disilylamides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, and sodium hexamethyldisilazide; trialkylamines such as triethylamine, diisopropylamine, and diisopropylethylamine; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic amines such as DBN and DBU; and hydrides such as lithium hydride, sodium hydride, and potassium hydride. The base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The term xe2x80x9cdeformylating agent,xe2x80x9d as used herein, represents a reagent capable of removing a formyl group from the nitrogen atom of a molecule during the course of a reaction. Examples of deformylating agents include a mixture of hydrogen fluoride, anisole, and 1,2-ethanedithiol; a mixture of hydrochloric acid and dioxane; a mixture of hydrochloric acid and methanol; hydrazine; hydrogen peroxide; and sodium hydroxide.
The term xe2x80x9cformylating agent,xe2x80x9d as used herein, represents a reagent capable of donating a formyl group to the nitrogen atom of a molecule during the course of a reaction. Examples of formylating agents include formic acid; 2,2,2-triethylformate; a mixture of formic acid and acetic anhydride; acetic formic anhydride; 2,3,4,5,6-pentafluorophenyl formate; ethyl formate; and a mixture of DMF and silica gel.
The term xe2x80x9cformyl,xe2x80x9d as used herein, represents xe2x80x94CHO.
The term xe2x80x9cmethylating agent,xe2x80x9d as used herein, represents a reagent capable of donating a methyl group during the course of a reaction. Preferred methylating agents for the practice of the instant invention include methyl triflate, dimethyl sulfate, methyl iodide, trimethyloxonium tetrafluoroborate, and diazomethane.
The term xe2x80x9coxidizing agent,xe2x80x9d as used herein, represents a reagent capable of converting an indoline to an indole. Preferred oxidizing agents for the practice of the instant invention include palladium on carbon, platinum on carbon, palladium hydroxide on carbon, salcomine with oxygen, barium manganate, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
The term xe2x80x9creducing agent,xe2x80x9d as used herein, represents a reagent capable of converting a formyl group to a methyl group. Preferred reducing agents for the practice of the instant invention include sodium borohydride; a mixture of lithium aluminum hydride and aluminum trichloride; triethylsilane; borane-methyl sulfide complex; a mixture of sodium cyanoborohydride and zinc iodide; and a mixture of zinc and hydrochloric acid.
The instant compounds can exist as therapeutically acceptable salts. The term xe2x80x9ctherapeutically acceptable salt,xe2x80x9d as used herein, represents salts or zwitterions of the compounds which are water or oil-soluble or dispersible; suitable for treatment of diseases without undue toxicity, irritation, and allergic response; commensurate with a reasonable benefit/risk ratio; and effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
Basic addition salts can be prepared during the final isolation and purification of the instant compounds by reacting the sulfonamide group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,Nxe2x80x2-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like, are contemplated as being within the scope of the instant invention.
All of the processes of the instant invention can be conducted as continuous processes. The term xe2x80x9ccontinuous process,xe2x80x9d as used herein, represents steps conducted without isolation of the intermediates.
Synthetic Processes
Abbreviations used in the descriptions of the schemes and the examples are: THF for tetrahydrofuran, DMAP for N,N-dimethylaminopyridine; DCC for dicyclohexylcarbodiimide; EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT for 1-hydroxybenzotriazole hydrate; and CDI for 1,1xe2x80x2-carbonyldiimidazole.
The methods of this invention will be better understood in connection with the following synthetic schemes which illustrate an embodiment of this invention. It will be readily apparent to one of ordinary skill in the art that the compounds of this invention can be prepared by substitution of the appropriate reactants and agents in the synthesis shown below. It will also be apparent to one skilled in the art that the order of the steps themselves can be varied. 
As shown in Scheme 1, indoline (1) can be converted to N-formylindoline (2) by treatment with a formylating agent. Representative formylating agents include formic acid, 2,2,2-trifluoroethylformate, acetic formic anhydride, and a mixture of formic acid and acetic anhydride. Examples of solvents used in these reactions include 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane, 1,2-dimethoxyethane, diethyl ether, THF, water, and mixtures thereof The reaction is conducted at about 25xc2x0 C. to about 65xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 4 hours.
N-Formylindoline (2) can be converted to 1-formyl-5-indolinesulfonyl chloride (3) by treatment with chlorosulfonic acid and thionyl chloride. Examples of solvents used in these reactions include dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and 1,2-dimethoxyethane. The reaction is conducted at about 0xc2x0 C. to about 85xc2x0 C. Reaction times are typically about 2 to about 6 hours.
1-Formyl-5-indolinesulfonyl chloride (3) can be converted to compounds of formula (5) by treatment with compounds of formula (4) and a base. Representative bases include sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate. Examples of solvents used in these reactions include ethyl acetate, isopropyl acetate, THE, diethyl ether, carbon tetrachloride, and chloroform. The reaction is conducted at about 20xc2x0 C. to about 50xc2x0 C. and depends on the conditions chosen. Reaction times are typically about 6 to about 24 hours. 
As shown in Scheme 2, compounds of formula (5) can be converted to compounds of formula (6) by treatment with a reducing agent. Representative reducing agents include borane-methyl sulfide complex, sodium borohydride, a mixture of lithium aluminum hydride and aluminum trichloride, and a mixture of sodium cyanoborohydride with zinc iodide. Examples of solvents used in these reactions include THF, diethyl ether, 1,2-dimethoxyethane, and methyl tert butyl ether. The reaction is conducted at about xe2x88x925xc2x0 C. to about 35xc2x0 C. Reaction times are typically about 1 to about 4 hours.
Conversion of compounds of formula (6) to compounds of formula (7) can be accomplished by treatment with an oxidizing agent. Representative oxidizing agents include palladium on carbon, platinum on carbon, palladium hydroxide on carbon, salcomine and oxygen, barium manganate, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Examples of solvents used in these reactions include THF, diethyl ether, 1,2-dimethoxyethane, methanol, and methyl tert butyl ether. The reaction can be conducted at about xe2x88x925xc2x0 C. to about 100xc2x0 C. and depends on the method chosen. Reaction times are typically about 8 to about 24 hours. 
An alternate route to compounds of formula (7) is shown in Scheme 3. Compounds of formula (5) can be converted to compounds of formula (8) by treatment with a deformylating agent. Representative deformylating agents include hydrochloric acid, hydrochloric acid in dioxane, hydrogen peroxide, and sodium hydroxide. Examples of solvents used in these reactions include methanol, ethanol, isopropanol, and butanol. The reaction is conducted at about 20xc2x0 C. to about 60xc2x0 C. and depends on the method chosen. Reaction times are typically about 5 minutes to about 24 hours.
Compounds of formula (8) can be converted to compounds of formula (9) using the various oxidative conditions described in Scheme 2.
Conversion of compounds of formula (9) to compounds of formula (7) can be accomplished by treatment with a methylating agent and a base. Representative methylating agents include dimethylsulfate, methyl iodide, and methyl triflate. Examples of bases include sodium hexamethyldisilazide, lithium hexamethyldisilazide, and potassium hexamethyldisilazide. Representative solvents include THF, diethyl ether, methyl tert butyl ether, and 1,2-dimethoxyethane. The reaction is conducted at about 0xc2x0 C. to about 25xc2x0 C. and depends on the method chosen. Reaction times are typically about 15 minutes to about 24 hours. 
As shown in Scheme 4, compounds of formula (7) can be converted to compounds of formula (10) by treatment with N,N-dimethylaminoacetyl chloride or N,N-dimethylaminoacetyl chloride hydrochloride in the presence of base. Representative bases include 4-pyrrolidinylpyridine, DMAP, triethylamine, diisopropylethylamine, and mixtures thereof. Typical solvents used in these reactions include dichloromethane, chloroform, THF, and ethyl acetate. The reaction is conducted at about 0xc2x0 C. to about 30xc2x0 C. and depends on the solvent chosen. Reaction times are typically about 2 to about 24 hours.
The invention will now be described in connection with other particularly preferred embodiments of Schemes 1-4, which are not intended to limit its scope. On the contrary, the invention covers all alternatives, modifications, and equivalents which are included within the scope of the claims. Thus, the following examples will illustrate an especially preferred practice of the invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.